The highly polymorphic human glucocorticoid receptor gene (GR) encodes the transcriptionally active GR isoform similar to murine GR, GR?, an isoform with reduced transactivation potential and GR, a dominant-negative isoform. Studies in human non-erythroid cells have identified that the pattern of GR isoform expression predicts cellular response to DXM in vitro. In addition, GR polymorphism is emerging as the leading cause for DXM unresponsiveness or for development of DXM resistance in patients with inflammatory and autoimmune diseases and in chronic depression. Clinical observations indicating that the GR ligand dexamethasone (DXM) stimulates erythropoiesis have been available since 1961. DXM is used as erythropoiesis stimulating agent (ESA) to rescue the deficient terminal erythroid (EB) maturation observed in patients with Diamond Blackfan Anemia (DBA), a congenic form of erythropoietin (EPO) resistant erythroid aplasia often associated with mutations that result in ribosome insufficiency. However the effects of the various GR isoforms on terminal erythroid maturation and whether these effects may determine DXM unresponsiveness in DBA patients (~50% of DBA patients do not respond to DXM) is still unknown. We recently identified that the rs6198 single nucleotide polymorphism (SNP) that stabilizes GRb mRNA is present with increased frequency in diseases of terminal EB maturation, associated with overproduction and erythrocytosis, as in polycythemia vera (55%) as well as underproduction (anemia) as in DBA (43%) (Varricchio et al, Blood 2011; 218; 425-436 and 473-474). These observations have generated a paradigm shift in our understanding of DXM as ESA highlighting the clinical need for additional studies on the effect of GR polymorphism on terminal EB maturation. We propose to characterize the biological activity of different GR isoforms in terminal EB maturation (Aim 1), to identify the microenvironmental and genetic factor(s) that regulate expression of these GR isoforms during terminal EB maturation (Aim 2) and to investigate the role exerted by individual GR isoforms in rescuing terminal EB maturation in DBA patients in vitro (Aim 3). We predict that these studies, by improving our understanding of the biology of GR in normal and DBA erythropoiesis, may identify more potent GR agonists (Aim 1) and pharmacological modulators (microenvironmental factors, Aim 2) to improve the treatment of DBA patients and possibly of other EPO resistant anemias. (End of Abstract)